Radiation Strategies Blaze a Trail for Better Outcomes in CNS Cancers and Beyond

Stephanie E. Weiss, MD, FASTRO

Several efforts are underway to examine novel radiation strategies in the treatment of patients with central nervous system (CNS) metastases spanning several tumor types, according to Stephanie E. Weiss, MD, FASTRO and Eric M. Horwitz, MD, FABS, FASTRO. These approaches have allowed for higher doses of radiation to be delivered to precise areas of the body, provide the potential for retreatment in certain cases, and created opportunities to reduce toxicities.

“It is pretty rare for us now to see a patient, look at them and say, ‘I am sorry, you have no options,’” Horwitz, the chair of radiation oncology, a professor, and Gerald E. Hanks Endowed Chair in Radiation Oncology, said. “We have many different ways to do things now. We can retreat patients with implants; use stereotactic body radiotherapy [SBRT], for prostate cancer and for other cancers; and we can do pulsed low-dose rate [LDR] intensity-modulated radiotherapy [IMRT] for a recurrent prostate cancer or other cancer. We have all these options that just did not exist before and it is all [because of] clinical trials that were done here, [at Fox Chase Cancer Center,] and elsewhere.”

In an interview with OncLive®,Horwitz, and Weiss, the chief of the Division of Neurologic Oncology, a professor in the Department of Radiation Oncology, and the director of the Radiation Oncology Residency and Fellowship Training Program at Fox Chase Cancer Center, discussed ways to leverage radiation in the treatment of CNS metastases, areas of active investigation, and different available strategies that are improving outcomes for patients with cancer.

OncLive®: What are some of the efforts being made to leverage the use of radiation in an attempt to control metastatic disease that has spread to the brain?

Weiss: One of the big questions we wish to address is: Are there any systemic therapies that work, either in lieu of, or synergistically with, radiation that [can] help control metastatic brain disease? [To this end,] about 10 to 15 years ago, we started to see some therapies [emerge] for lung cancer that do not replace radiation but work synergistically to help control metastatic brain disease.

Patients are living longer because [investigators in the field of] medical oncology are doing a good job at [developing] new drugs that work throughout the body. [However, now,] disease that has spread to the brain has become a bigger issue. Most of the time, these drugs do not penetrate the brain, so we rely on radiation to treat these diseases.

Some central nervous system [CNS]–penetrating drugs help, and a lot of data suggest that combining them with radiation not only helps better control what is going on in the brain, but [it may achieve] an immunologic response that helps better control disease elsewhere in the body. You get this immunologic stimulation; once the radiation kills the tumor, these immunotherapies essentially pick up on the antigen from the tumor cells and work elsewhere in the body to help clean up the disease.

That is one area that is becoming very interesting. Now, we are also starting to see some drugs in other disease sites, such as breast cancer, that seem to work in the brain. [These agents are certainly] having an impact [on patient outcomes].

What are some of the factors that you consider when choosing among the different radiation approaches available? How do you approach sequencing in terms of radiosurgery?

Weiss: When you have a patient with brain metastases, you want to choose the kind of radiation that is going to [best] benefit them. One [option is] to do whole brain radiation therapy. The advantage [to this approach] is that it helps prevent new lesions from popping up. [However,] the disadvantage is that the adverse effects [AEs] can include significant fatigue, and even some neurocognitive changes.

In recent years, we have realized that for an ever-increasing number of patients, we are able to do radiosurgery instead; this is focused treatment on just the individual lesions. As things have evolved, the question has become: What do we do for patients who wind up needing surgery for their lesion because it is either very large and is causing symptoms that need to be immediately relieved, or we need to get the tissue to know exactly what we are dealing with?

In the past 10 years, people have taken the patient to surgery and then [performed] radiosurgery. Interestingly, the [disease] control in, and the AEs [experienced by] patients who [undergo] surgery followed by radiosurgery do not seem to be as favorable [as what is seen in] those who just get radiosurgery alone to intact brain lesions. As such, the big question now is: What happens if we reverse the sequencing?

[When appropriate], we take patients to receive radiosurgery up front. Then, we take them to surgery. The preliminary [findings with this sequence] suggest that the [disease] control is better, the risk of spread to the cerebral spinal fluid is lower, and [there are fewer] AEs.

At Fox Chase Cancer Center, [we are conducting] a randomized trial to compare the sequencing of pre- vs post-operative radiosurgery for patients with brain metastases; we are working with a national consortium to do this. That is a very exciting [effort], and it will help us determine what [approaches] are best for individual patients.

What are some areas of active investigation that you’re excited about? What are the next steps for radiation approaches?

Weiss: Many different tumors involve the CNS, and the strategies [to treat these tumors] are very different because of their behavior. In general, we are always looking to see whether any drugs can help treat these lesions. It is very difficult to get drugs [into the CNS]. We are always looking for drugs that are able to penetrate the CNS and are also efficacious.

Another exciting [area of research is] utilizing the same radiation, but [taking a closer look at] the rate at which we deliver it. Radiodynamic therapy [is another area of active investigation], as is pulsed low-dose radiotherapy, where you get the same dose, [but] each session is delivered much more slowly. This impacts the cellular response, both for the normal tissue and the tumor tissue. The thought is that the therapeutic ratio, the ability to kill the tumor but spare normal tissue, is potentially better with this therapy.

Shifting specifically to prostate cancer, what recent developments have been made with radiation?

Horwitz: For prostate cancer, we are using hypofractionated treatment. In the old days, men with prostate cancer were treated with 8 to 9 weeks of radiation. [Currently], that is almost never done. The only people who receive 8 weeks of radiation are those who just have physically large prostates and significant baseline urinary symptoms. Everyone else receives short courses of treatment. Our standard is 2.5 weeks of external radiation with SBRT.

We are a big radiation implant center, so we also do temporary high-dose rate [HDR] prostate implants. They are not new, but they are not commonly done in the United States because they require more infrastructure. We are privileged to have our own operating room in the middle of the radiation department that is a general anesthesia–capable shielded vault; we can do HDR prostate implants in [there]. We do many prostate implants, mostly for men who have smaller prostate cancers; [in those cases,] it is 2 implants, usually [done] a week apart.

We will use that [approach] for smaller cancers. For men with bigger cancers, we will combine IMRT with the implant. A lot of data have come out, both here in the United States, and internationally, that support the use of combination treatments in men who have very big, aggressive prostate cancers; [these regimens] work very well.

Back when I was training, there were no options for men who had biopsy-proven local recurrences, meaning they had received treatment in the past with conventional external beam radiation and they had recurrence in the prostate. Once you had radiated a patient’s prostate, you could not radiate it again. Now, we are able to safely retreat [patients]. We can do this with an implant.

The other thing that Dr Weiss mentioned was a study that our colleagues had started here, a few of years ago, [that focused on] pulsed LDR IMRT. This approach [uses] the same doses of radiation, but we are giving it in a way that is safe for tissue that has already received radiation; it is also biologically effective in retreating the cancer. [This strategy] has actually given us the ability to retreat [patients] who, in the past, [could not be] retreated. You can do that now, and the safety is amazing. [Patients] really tolerate this treatment well.

Another effort at your institution is examining the addition of a high-dose rate (HDR) boost after IMRT. Could you speak to this a bit?

Weiss: We know that biochemical control for prostate cancer, after receiving a more typical LDR prostate brachytherapy therapy boost, is better. [However], these patients who receive the LDR boost after IMRT, experience worse urinary AEs and physical function scores. As such, we are now looking at our population who [receive] HDR, which, as Dr Horwitz said, is something that we are particularly skilled at doing at Fox Chase that has not been widely adopted yet. The thought is that there will be less toxicity than [what has been seen in those] who have received the LDR boost.

Horwitz: We can safely give big doses of radiation with less exposure to the normal tissue that surrounds whatever we are treating. For prostate cancer, it is the bladder and rectum; however, for other sites, it is whatever is adjacent to the tumor. We want to give the full dose of radiation to the cancer. In a perfect world, the [areas] around the cancer, would get nothing; however, that is a physical impossibility. We are trying to [find] the best balance. How do we deliver the most radiation to the cancer so that it is effective and kills the cancer, while protecting the normal tissue and minimizing the AEs for our patients? Radiation oncologists [are coming] together [to find novel] options that just did not exist before.